4,7 dioxo 12h-cyclopenta (2, 1-8:3,4 g&#39;)diquinoline 2,9 dicarboxylic acid derivatives

ABSTRACT

This invention relates to novel compounds, methods for preparing them and pharmaceutical compositions containing them, and a process for the prophylactic treatment of allergic conditions employing said compositions. These novel compounds are embraced by the formula   WHEREIN R1 and R2 are selected from the group consisting of hydrogen and lower alkyl of 1 through 6 carbon atoms. The compounds (I), above, are formulated with pharmaceutical carriers for oral, parenteral, rectal and local administration with insufflation being the preferred method. The compositions are useful in the prophylactic treatment of sensitized humans and mammals for allergy and all anaphylactic reactions of a reagin or non-reagin mediated nature.   WHEREIN R is selected from the group consisting of hydrogen, lower alkyl of 1 through 3 carbon atoms, phenyl, an alkali metal, aluminum, calcium, magnesium, or an amine cation, said amine being selected from the group consisting of ammonia, an alkyl amine, ethanolamine, tris-(hydroxymethyl)aminomethane, D-threo-2amino-1-(p-nitrophenyl)-1,3-propanediol, N,Nbis(hydroxyethyl)piperazine, 2-amino-2-methyl-1-propanol, 2amino-2-methyl-1,3-propanediol and 2,2-bis(hydroxymethyl)-2,2&#39;&#39;, 2&#39;&#39;&#39;&#39;-nitrilotriethanol; Z is selected from the group consisting of hydrogen, phenyl, and lower alkyl of 1 through 3 carbon atoms; A is selected from the group consisting of

United States Patent [191 Hall et al. I

[ 54] TJ-DIOXO 12II-CYCLOPENTA 2, 1-8:3,4 DIQUINOLINE 2,9 DICARBOXYLIC ACID DERIVATIVES [75] Inventors: Charles M. Hall; Herbert G.

Johnson, both of Kalamazoo, Mich.

[73] Assignee: The Upjohn Company, Kalamazoo,

Mich.

[22] Filed: Nov. 20, 1972 [21] Appl. No.: 308,035

52 us. CL... 260/286 R, 260/268 PC, 260/270 R, 260/287, 260/465 260/47g a, 260/485 R, 260/571, 260/576, 260/578, 424/258, 424/245 [51] Int. Cl. C07d 39/00, C07d 51/70 [58] Field 01 Search ..--260/287 R, 270 R, 286 R [56] References Cited 2 UNITED STATES PATENTS 2,520,041 8/1950 Lisl 260/287 R FOREIGN PATENTS OR APPLlCATlONS 2,130,403 12/1971 Germany ..l 260/287 2,145,423 3/1972 Germany 260/287 Primary Examiner-Donald G. Daus Assistant ExaminerDavid E. Wheeler Attorney, Agent, or Firm-William A. Hodes; Willard L. Cheeseman [5 7] ABSTRACT This invention relates to novel compounds, methods for preparing them and pharmaceutical compositions containing them, and a process for the prophylactic treatment of allergic conditions employing said compositions. These novel compounds are embraced by June 28, 1974 the formula JUL I wherein R and R are selected from. the group consisting of hydrogen and lower alkyl of 1 through 6 carbon atoms.

The compounds (1), above, are formulated with pharmaceutical carriers for oral, parenteral, rectal and local administration with insufflation being the preferred method. The compositions are useful in the prophylactic treatment of sensitized humans and mammals for allergy and all anaphylactic reactions of a reagin or non-reagin mediated nature. I

3 Claims, N0 Drawings 1 4,7 DIOXO lZH-CYCLOPENTA (2, 1-8:3,4 g DIQUINOLINE 2,9 DICARBOXYLIC ACID DERIVATIVES BRIEF SUMMARY OF THE INVENTION This invention relates to novel compounds, methods for preparing them and pharmaceutical compositions containing them, and a process for the prophylactic treatment of allergic conditions employing said compositions.

In accordance with this invention the compounds of Formula 1, above, are represented by the structural formulae la and lb, below, which are its tautomeric forms. It is to be understood that the compounds of this invention are likely to be mixtures of all tautomeric forms, the percentages of each tautomer being dependent on the nature of R and Z and the physical environment of the compound. I

azine, 2-amino-2-methyll -propanol, 2-amino-2-methyll ,3-propanediol and 2,2-bis(hydroxymethyl)- 2,2',2"-nitrilotriethanol; Z is selected from the group consisting of hydrogen, phenyl, and lower alkyl of 1 through 3 carbon atoms; A is selected from the group Quit i wherein R' and R are selected from the group consisting of hydrogen-and lower alkyl of 1 through 6 carbon atoms.

The terms employed throughout this specification have the meaning oridinarily understood in the chemical art. Examples of alkali metals include lithium, sodium and potassium. Examples of lower alkyl of from 1 through 3 carbon atoms include methyl, ethyl, propyl and isopropyl. Examples of lower alkyl of 4 through 6 carbon atoms include butyl, pentyl and hexyl and the isomeric forms thereofExamples of alkyl amine include monoethylamine, monomethylamine, mono- .propylamine, monoisopropylamine, diethylamine, di-

methylamine, dipropylamine, diisopropylamine, triethylamine,"trimethylamine, tripropylamine and triisopropylamine. Examples of amine cation include all ymethyl)-aminomethane,

PROCESS A The compounds of the formula A 13i ROOC l [j wooon ki wherein A has the same meaning as above and R has the same meaning as above except hydrogen, are prepared by the steps comprising l. mixing a corresponding compound of the formula QOOCC E CCOOQ wherein Q is lower alkyl of 1 through 3 carbon atoms or phenyl with a corresponding compound of the formula A HQN- NH2 .2 a. H. V A wherein A has the same meaning as above, to yield a corresponding compound of the formula A QOOOC/ ooooo ooorrl J liHooo wherein A and Q have the same meaning as above;

2. heating a thus produced corresponding compound resulting fromstep (l) to yield a corresponding com pound of Formula I, above.

A third step is required for preparing the compounds of thefor n l H H Hoes-@Ofi ooH 3 wherein A has the same meaning as above, namely, hydrolyzing a corresponding compound produced in the manner described in step (2) immediately above and having the formula wherein A and Q have the same meaning as above, e.g.,

with an alkali metal hydroxide and then adding thereto a strongacid.

l. The first step of Process A'comprises mixing a dialkylacetylene dicarboxylate (IV) with a compound of Formula [11, e.g., a 2,7-diaminofluorene, in a molar ratio of approximately 2 of the former (IV) to l of the latter (Ill) reactants, to yield a corresponding diadduct, a tetraalkyl 2,2'-[(fluorene-2,7-diyl)diimino]dibutendioate (ll). Molar ratios in excess of 2:1 (e.g., 3:1 to 5:1) are also satisfactory. Appropriate solvents for the reaction are alkanols of from ,l through 6 carbon atoms, preferably of from 1 through 3 carbon atoms, benzene, diethylether, dioxane, tetrahydrofuran, or any other solvent which puts both reactants (IV and III) into solution and allows formation of the desired compound (ll). Generally the reaction proceeds readily at room temperature and can be accelerated by increasing the temperature to about 100C.

2. In this step, ring closure of a diadduct (ll) produced in step (1) and formation of the desired corresponding dialkyl l ,4,7, l -tetrahydro-4,7-dioxo-12H- cyclopenta[2, l -g:3,4 g'1diquinoline-2,9-dicarboxylate (l) is accomplished by heating said diadduct (ll) at a relatively high temperature. The neat diadduct (ll) can be heated directly, but it is preferable to put it into a solvent that can function as a heat transfer medium. Any high boiling inert solvent such as a mineral oil, hexamethylphosphoric triamide, diphenyl ether, or Dowtherm A (a commercial mixture of diphenyl and diphenyl ether), is suitable. The ring cyclization step is preferably carried out at temperatures of from about 220C. to about 280C, although lower or higher temperatures can be employed, if desired. Particularly preferred solvents are Dowtherm A or diphenyl ether, which boil at about 250C, thus enabling the ring cyclization to occur during reflux. (At this point of the process, different esters'can be prepared at the R position of the carboxy group, e.g., by a standard transesterification reaction.)

- An advantage of the elevated temperature during the ring cyclization step is that any adduct fonned in the preceding step which is not in a position to cyclize, since it is trans to the benzene ring, is isomerized to the cis configuration during the heating, thereby allowing substantial yields of the desired compound to be produced. This trans adduct preparation occurs more frequently when an aprotic solvent and a dialkylacetylene dicarboxylate are used in the adduct formation step.-

3. In the third step of the process, a 2,9-dicarboxylate ester (l) resulting from step (2) is converted to its corresponding 2,9-dicarboxylic acid (I) by treatment with a base (e.g., by heating the former with an aqueous so-.

lution of an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide), then adding tothe reaction mixture 21 strong acid (such as trifluoroacetic acid, sulfuric acid, nitric acid and the like) to give a solid 2,9-dicarboxylic acid (I) that can be collected, for example, by filtration. A thus produceddicarboxylic acid (I) can be readily converted to acorresponding amine salt or alkali'metal derivative by contacting the former with two' equivalents of thc dcsired amine or alkali metal and heating in a sufficient amount of water to effect solubilization. The crystalline salts can be precipitated by the addition of methanol.

PROCESS B The compounds of the formula 1. mixing, in the presence of an acid catalyst, a corresponding compound of the formula wherein Q and Z have the same meaning as above, with a corresponding compound of the formula A mN-@ @NH;

wherein A has the same meaning as above, yield a corresponding compound of the formula wherein A, Q and Z have the same meaning as above; 2. heating a thus producedcorresponding compound resulting from step (1) to yield a corresponding compound of Formula I, above A third step is required for preparing the compounds of the formula H /A )Tooon L v p I III E N aooo wherein A and Z have the same meaning as above, namely, hydrolyzing a corresponding compound produced in the manner described in step (2) immediately above and having the formula wherein A, Q and Z havethe same meaning as above, e.g., with an .alkali metal hydroxide and then adding thereto a strong acid.

l. The first step of Process B comprises mixing an alkali metal salt of a di(alkyl or phenyl) oxalacylate (IV') with a 2,7-diaminofluorene (III), in a molar ratio of at least 2 of the fonner (IV) to l of the latter (III) reactants, in the presence. of an acid catalyst, to yield a corresponding diadduct, a tetraalkyl 2,2'-[(9-oxofluorene- 2,6-diyl)diimino] bis 3-alkyl(or phenyl) butenedioate] (ll). Molar ratios in excess of 2:l (e.g., 3: l; to

5:1) are also satisfactory. When using the oxaloacylate reagent (IV') to form the diadduct, there should be a sufficient amount of acid present to-protonate the oxaloacylate carbon and catalyze the removal of the keto grouping as water. The acid can also serve as a solvent for the two reagents as well. For example, glacial acetic acid, propionic acid, p-toluene sulfonic acid, and butyric acid are acids which can be used. If a further rea gent is needed to place the two reactants into solution, (or a cosolvent desired), benzene, toluene, diethyl ether, dioxane, tetrahydrofuran, or alcohols from one to about four carbon atoms can be employed. The length of time for the formation of the diadduct is temperature dependent. At room temperature the reaction proceeds rather slowly, but as the temperature is raised, reaction time is decreased. Acceptable reaction times are achieved at temperatures ranging from about 40 to about 70C., although reaction temperatures can be above 100C. if desired.

2, 3. These steps of Process B are the same as the corresponding steps of Process A, above.

All of the compounds included within Formula I, above, and the intermediates therefor, can be isolated from their respective reaction mixtures by conventional means, for example, when a water-miscible solvent is used, by pouring the reaction mixture into water and separating the resulting precipitate by filtration or by extraction with water-immiscible solvents. Additional purification of the products can be accomplished by conventional means, for example, by elution chromatography from an adsorbent column with a suitable solvent such as acetone, ethyl acetate, ether, methylene chloride and Skellysolve B (hexanes), mixtures and combinations of these solvents; also be gradient elution chromatography from an adsorbent column with a suitable mixtureof solvents, such as, methylene chloride- Skellysolve B, acetone-Skellysolve B, and the like.

The novel compounds (I) of this invention have antiallergic (especially anti-asthmatic) activity, inhibiting a positive Passive Cutaneous Anaphylactic (PCA) test induced by the rat immunochemical counterpart of human IgE (regain), and is considered indicative of inhibiting human allergic activity. This activity is apparent when these compounds are tested for their inhibition of the rat PCA reaction. The PCA assay is described by I. Mota in Immunology 5111 (1962).

DETAILED DESCRIPTION Preparation 1: 2,7-diaminofluroen-9-ethyl-9-ol (III) To a suspension of 2,7-diaminofluoren-9-one (III) (prepared as in Ann. 390, 225) in 200 ml. of tetrahydrofuran, 32 ml. of a 3 M ether solution of ethyl magnesium bromide is carefully added. The reaction mixture is stirred at room temperature for about 1 hourand ,then heated at reflux for about 1 hour. The mixture is allowed to cool and then poured into a mixture of ice and ammonium chloride. The solid 2,7- diaminofluoren-9-ethyl-9-ol (III) is collected by filtration.

Following the procedure of Preparation 1 but substituting an equivalent amount of another Grignard reagent, such as 1. methyl magnesium bromide,

2. propyl magnesium bromide,

. isopropyl magnesium fluoride, butyl magnesium bromide,

. isobutyl magnesium iodide,

. sec. butyl magnesium bromide, t. butyl magnesium chloride,

. pentyl magnesium bromide,

. isopentyl magnesium bromide,

10. t. pentyl magnesium chloride,

ll. hexyl magnesium bromide, etc., yields, respectively, I

l. 2,7-diaminofluorene-9-methyl-9-ol (Ill),

2. 2,7-diaminofluorene-9-propyl-9-ol (III),

. 2,7-diaminofluoren-9-isopropyl-9-ol (III), 2,7-diaminofluorene-9-butyl-9-ol (III),

. 2,7-diaminofluoren-9-isobutyl-9-ol (III),

. 2,7-diaminofluorene-9-sec. butyl-9-ol (III), 2,7-diaminofluorene-9-t. butyl-9-ol (III),

. 2,7-diaminofluorene-9-pentyl-9-ol (III),

. 2,7-diaminofluoren-9-isopentyL9-ol (III),

10. 2,7-diaminofluorene-9-t. pentyl-9-ol (III),

1 l. -2,7-diaminofluorene-9-hexyl-9-ol (III), etc. Preparation 2 2,7-diamino-9-ethylidenefluorene (III) In 250 ml. of benzene containing 0.1 g. of p-toluenesulfonic acid as catalyst, 2 g. of 2,7-diamino-9-ethyl-9- 01 (III) (obtained as in Preparation 1, above) is heated at reflux with the constant removal of water. When the theoretical amount of water is collected, the reaction mixture is cooled. The reaction mixture is washed with about ml. of saturated aqueous sodium bicarbonate solution and about 100 ml. of water. The organic layer is dried with anhydrous sodium sulfate and the solvent removed to give 2, 7-diamino-9- ethylidenefluorene (III).

Following the procedure of Preparation 2 but substituting another 2,7-diamino-9-alkyl-9-ol (Ill) for 2,7-diamino-9-ethyl-9-ol (III), such as l. 2,7 diamino-9-propyl-9-ol (III),

2. 2,7-diamino-9-butyl-9-ol (III),

3. 2,7-diamino-9-isobutyl-9-ol (III),

4. 2,7-diamino-9-pentyl-9-ol (III),

5. 2,7-diamino-9-isopentyl-9-ol (III),

2,7-diamino-9-hexyl-9-ol (III), 2,7-diamino-9-isohexyl-9-ol (III), etc., yields, respectively,

l. 2,7-diamino-9-propylidenefluorene (Ill),

2. 2,7-diamino-9-butylidenefluorene (III),

3 2,7-diamino-9-isobutylidenefluorene (III),

4. 2,7-diamino-9-pentylidenefluorene (III),

5. 2,7-diamino 9-isopentylidenefluorene (III),

6. 2,7-diamino-9-hexylidenefluorene (III),

7. 2,7-diamino-9-isohexylidenefluorene (III), etc. Preparation 3-2,7-diamino-9-ethylfluorene (III) A suspension of 2 g. of 2,7-diamino-9-ethylidenefluorene (III) (obtained as in Preparation 2, above) and 0.1 g. of 5% palladium on charcoal catalyst in 200 ml. of methanol is shaken under hydrogen at a pressure of 40 pounds/square inch until hydrogen uptake ceases. Removal of the catalyst and the solvent leaves 2,7- diaminofluorene (III).

Following the procedure of Preparation 3 but substituting another 2,7-diamin0-9-alkylidenefluorene (III) for 2,7-diamino-9-ethylidenefluorene (III), such as 1. 2. 3. 4. etc.,

ethylfluorene (III) (obtained as in Preparation 3) is treated with an excess 1.6 ml. in hexane) of butyl lithium. Methyl iodide is added to the reaction mixture,

which is stirred for about 1 hour and then poured into ice water. The resulting mixture is extracted with methylene chloride. The organic phase is dried over anhydrous sodium sulfate and the solvent removed to give 2,7-diamino-9-ethy1-9-methylfluorene (111).

Following the procedure of Preparation 4 but substituting another 2,7-diamino-9-alkylfluorene (III) for 2,7-diamino-9-ethylfluorene (III) and another alkyl iodide for methyl iodide, such as l. 2,7-diamino-9-methylfluorene (III) and propyl iodide,

2. 2,7-diamino-9-butylfluorene (Ill) and methyl iodide, I

3. 2,7-diamino-9-propylfluorene (III) and pentyl iodide,

4. 2,7-diamino-9-pentylfluorene (Ill) and butyl iodide,

5. 2,7-diamino 9-isohexylfluorene (III and isobutyl iodide, etc., yields, respectively,

1. 2,7-diamino-9-methyl-9-propylfluorene (Ill),

2. 2,7-diamino-9-butyl-9-methylfluorene (III),

3. 2,7-diamino-9-pentyl-9-propylfluorene (III),

4. 2,7-diamino-9-butyl -9-pentylfluorene (III),

5. 2,7-diamino-9-isobutyl-9-isohexylfluorene (III),

etc.

EXAMPLE 1: 1,4,7, 1 O-tetrahydro-4,7, l2-trioxol 2H-cyclopenta- [2,1-g:3,4-g]diquinoline-2,9-dicarboxylic acid (1) PART A: Tetramethyl 2,2'-[(9-oxofluorene-2,7-diyl)diiminol-dibutendioate PART B: Dimethyl 1,4,7,10-tetrahydro-4,7,12-trioxo-l2H- cyclopenta[2,1-g:3,4-g']diquinoline-2,9-dicarboxylate 2 g. of the compound (II) obtained in Part A, above,

is carefully added to 100 ml. of Dowtherm A refluxing at about 250C. The reaction mixture is refluxed for about 5 minutes, then allowed to cool to room temperature. The resulting solid is collected by filtration and washed well with acetone; it weighs 1.4 g. and melts above 310C. The low solubility of this compound in common organic solvents precludes meaningful elemental analysis. Its infrared absorption spectrum (Nujol) is consistent with the expected product, dimethyl 1,4,7,10-tetrahydro-4,7,l2-triox0-12H- cyclopenta[ 2, l -g: 3,4-g ]diquinoline-2,9-dicarboxylate (I).

PART C: Disodium l ,4,7,lOtetrahydro-4,7, l2-trioxo-12H- cyclopenta[2, 1-g:3,4-g' ]diquinoline-2,9-dicarboxylate 1 g. of the diester compound (I) obtained in Part B, above, is heated at reflux for about 1 hour in 10 ml. of l N aqueous sodium hydroxide solution. The reaction mixture is allowed to cool to room temperature to yield disodium l,4,7,10-tetrahydro-4,7,l2-trioxo-12H cyclopenta[2, 1 -g:3,4-g' ]diquinoline-2,9-dicarboxylate (1).

PART D: 1,4,7,10-Tetrahydro-4,7,12-trioxo-12H-cyclopenta- [2,1-g:3,4-g']diquinoline-Z,9-dicarboxylic acid (I) The cooled solution of the disodium compound (I) obtained in Part C, above, is acidified with concentrated hydrochloric acid to pH 3. The resulting solid is collected by filtration to give 1 g. of 1,4,7,]0- tetrahydro-4,7, l 2-trioxol 2H-cyclopenta[ 2, l-g:3 ,4- g']diquinoline-2,9-dicarboxylic acid (1).

EXAMPLE 2: 1,4,7,10Tetrahydro-4,7,l2-trioxo-l2H-cyclopenta- [2,l-g:3,4-g]diquinoline-2,9-dicarboxylic acid (1) Following the procedure of Example 1 but substituting diethylacetylene dicarboxylate (IV) [Prepared as in J. Chem. Soc. 678 (1948)]-for dimethylacetylene dicarboxylate in Part A thereof, yields tetraethyl 2,2- [(9-oxofluorene-2,7-diyl)diimino]di-butendioate (II), diethyl l ,4,7,1O -tetrahydro-4,7,12-trioxo-l2H- cyclopenta[2,1-g:3,4-g]diquinoline-2,9-dicarboxylate I), disodium 1,4,7,l0-tetrahydro-4,7,12-trioxo-12H- cyclopenta[ 2, l-g: 3,4-g' ]diquinoline-2,9-dicarboxylate (I) and 1,4,7,10-tetrahydro-4,7,l2-trioxo-12H- cyclopenta[2,1-g:3,4-g]diquinoline-Z,9-dicarboxylic acid (I).

EXAMPLE 3: v 1 ,4,7,l0-Tetrahydro-4,7,12-trioxo-12H-cyclopenta- [2,l-g:3,4-g']diquinoline-2,9-dicarboxylic acid (1) Following the procedure of Example 1 but substituting dipropylacetylene dicarboxylate (IV) [prepared as in J. Chem. Soc. 678 (1948)] as one of the starting materials in Part A thereof, and potassium hydroxide for sodium hydroxide in Part C thereof, yields tetrapropyl 2,2'-[(9-oxofluoroene-2,7-diyl)diimino]di-butendioate (ll), dipropyl 1,4,7, 1 0-tetrahydro-4,7, l 2-trioxo- 1 2H- cyclopenta[2,1-g:3,4-g' ]di-quinoline-2,9-dicarboxylate (I), dipotassium 1,4,7, 1 O-tetrahydro-4,7, 1 2-trioxo- 12H-cyclopenta[ 2, 1 -g:3 ,4-g ]diquino1ine-2,9- dicarboxylate (I) and 1,4,7,10-tetrahydro-4,7,12- trioxo-l2H-cyclopenta[2,1-g:3,4-g]diquinoline-2,9- dicarboxylic acid (I).

EXAMPLE 4: l ,4,7,10-Tetrahydro-4,7-dioxo-12H-cyclopenta-[2,1- g:3,4-g' ]diquinoline-2,9-dicarboxylic acid 1) Following the procedure of Example 1 but substituting 2,7-diaminofluorene ([11) (prepared as in Ber. 64, 1793) in Part A thereof, yields tetramethyl 2,2- [(fluorene-ZJ-diyl)diiminoldi-butendioate (11), dimethyl 1,4,7,10-tetrahydr-4,7-dioxo-12H- cyclopenta[2,1-g:3,4-g']diquinoline-2,9-dicarboxylate (1), disodium 1 ,4,7,10-tetrahydro-4,7-dioxo-12H- cyclopenta[2,1-g:3,4-g]diquinoline-2,9-dicarboxylate (l) and 1,4,7,10-tetrahydro-4,7-dioxo-l2H- cyclopenta[2,1-g:3,4-g']diquinoline-Z,9-dicarboxylic acid (1).

EXAMPLE 5: 1 ,4,7, 1 0-Tetrahydro-4,7-dioxo-12-01-12H- cyclopenta[2,1-g:3,4-g]diquinoline-2,9-dicarboxylic acid (1) Following the procedure of Example 1 but substituting diisopropylacetylene dicarboxylate (1V) [prepared as in J. Chem. Soc. 678 (1948)] and 2,7-diaminofluoren-9-ol (lll) (prepared as in Ann. Chim. 14, 5) as starting materials in Part A thereof, yields tetraisopr'opyl 2,- 2-[fluoren-9-ol-2,7diyl)dimino]dibutendioate diisopropyl ,4,7, l0-tetrahydro-4,7-dioxo-1 2-ol-12H- cyclopenta[2,1-g:3,4-g']diquinoline-2,9-dicarboxylate (l), disodium l,4,7,10-tetrahydro-4,7-dioxo-12-01- l2H-cyclopenta[2, l-g:3,4-g']diquinoline-2,9- dicarboxylate (I) and 1,4,7,lO-tetrahydro-4,7-dioxol 2-01-1 2H-cyclopenta[2,1 -g:3,4-g]diquinoline-2,9- dicarboxylic acid (1).

EXAMPLE 6:

I,4,7,l0-Tetrahydro-4,7-dioxo-12-methyl-12-ol12H- cyclopenta[2, 1-g:3,4-g' ]diquinoline-2,9-dicarboxylic acid (1) Following the procedure of Example 1 but substituting dibutylacetylene dicarboxylat'e (1V) [prepared as in J. Chem. Soc. 678 (1948)] and 2,7-diaminofluoren-9- methyl-9-ol (lll) (prepared as in Preparation 1, above) as starting materials in Part A thereof, yields tetrabutyl 2,2-[(fluoren-9-methyl-9-ol-2,7-diyl)diiminoldibutendioate (l1), dibutyl 1,4,7,10-tetrahydro-4,7-dioxo-12- methyl-12-01-12H-cyclopenta[2,1-g: 3,4-

g]diquinoline-2,9dicarboxylate (l), disodium 1,4,7,1-

0-tetrahydro-4,7-dioxo-1 2-methyll 2-01- 12H- cyclopenta[2,1-g: 3,4-g']diquinoline-2,9-dicarboxylate (I) and 1 ,4,7,10-tetrahydro-4,7-dioxo-12-methyl-12- ol- 1 2H-cyclopenta[ 1 ,2-g: 3,4-g]diquinoline-2,9- dicarboxylic acid (1).

EXAMPLE 7: 1 ,4,7, l 0-Tetrahydro-4,7-dioxo'- l 2-ethyl- 1 2-01- 1 2H- cyclopenta[ 2, l -g:3 ,4-g' ]diquinoline-2,9-dicarboxylic acid (1) Following the procedure of Example 1 but substituting 2,7-diaminofluoren-9-ethyl-9-ol ([11) (obtained as in Preparation 1,-above) for 2,7-diaminofluoren-9-one (111) in Part A thereof, yields l,4,7,l0-tetrahydro-4,7-

dioxo-l 2-ethyl-12-ol-1 2H-cyclopenta[2, l-g:3,4- g]diquinoline-2,9-dicarboxylic acid (1).

Following the procedure of Example 7 but substituting 2,7-diaminofluoren-9-isopropyl-9-o1 (111). yields 1,- 4,7, -tetrahydro-4,7-dioxo-l2-isopropyl-l2-ol-l2H- 118 cyc1openta[ 2, l-g: 3 ,4-g' ]diquinoline-Z,9-dicarboxylic acid 1).

EXAMPLE 8: 1 ,4,7,10-Tetrahydro-4,7 dioxo-12-ethylidene-l 2H- cyclopenta[ 2, l -g: 3,4g]diquinoline-2,9-dicarboxylic acid (1)) Following the procedure of Example 1 but substituting 2,7-diamino-9-ethylidenefluorene (111) (obtained as in Preparation 2, above)'for 2,7-diaminofluoren-9-one (III) in Part A thereof, yields 1,4,7,10-tetrahydro-4,7- dioxo-l 2-ethylidene-12H-cyclopenta[2, l-g:3,4- g]diquinoline-Z,9-dicarboxylic acid (1).

Following the procedure of Example 8 but substituting 2,7-diamino-9-propylidenfluorene (I11), yields 1,4,- 7,10-tetrahydro-4,7-dioxo-l2-propylidene-12H- cyclopenta[ 2, l -g: 3 ,4-g' ]diquinoline-2,9-dicarboxy1ic acid (1).

EXAMPLE 9: 1,4,7,lO-Tetrahydro-4,7-dioxo-12-ethyl-121-1- cyclopenta[2,1-g:3,4-g']diquinoline-2,9-dicarboxylic acid (1) Following the procedure of Example 1 but substituting 2,7-diamino-9-ethylfluorene (111) (obtained as in Preparation 3, above) for 2,7-diaminofluoren-9-one (III) in Part A thereof, yields l,4,7,10-tetrahydro-4,7- dioxo-12-ethyl-l2H-cyclopenta[2,l-g:3,4- g]diquinoline-2,9-dicarboxylic acid (1).

Following the procedure of Example 9 but substituting 2,7-diamino-9-isopropylfluorene (Ill), yields 1,4,7,- 10-tetrahydro-4,7-dioxo-12-isopropyl-l2H- cyclopenta[2,1-g:3,4-g ]-diquinoline-2,9-dicarboxylic acid (1).

EXAMPLE 10: 1,4,7, 1 0-Tetrahydro-4,7-dioxol 2-ethyll 2-methyll 2H-cyclopenta[2, 1-g:3,4-g' ]diquinoline-2,9- dicarboxylic acid (1) EXAMPLE 1 1: Di(tris-hydroxymethyl)methylammonium l ,4,7,10-tetrahydr0-4,7,12-trioxo-12H- cyclopenta[2,1-g:3,4-g']diquinoline-2,9-dicarboxylic acid (1) To 10ml of water, 1 g. of 1,4,7,10-tetrahydro-4,7- l2trioxo-12H-cyclopenta[2,1,-g:3,4-g]diquinoline-2,9- dicarboxylic acid (1) (prepared as in Example 1 is added. To this, 0.77 g. of tris-(hydroxymethyl)aminomethane is added. The mixture is heated for several minutes until solution is complete. The crystalline di(tris- (hydroxymethyl))-methylammonium 1 ,4,7, 10- tetrahydro-4,7,12-trioxo-121-1-cyclopenta[2,l-g:3,4-

g]diquinolinc-2,9-dicarboxylic acid (1) is precipitated by the addition of methanol to the mixture.

Following the procedure of Example 1 l but substituting another starting material for l,4,7,l-tetrahydro- 4,7,l2-trioxo-l2H-cyclopenta[2,l-g:3,4- g]diquinoline-2,9-dicarboxylic acid (I), such as 1 1,4,7,lO-tetrahydro-4,7-dioxo-12H- cyclopenta[2,1-g:3,4-g]diquinoline-2,9- dicarboxylic acid (I),

2. 1,4,7, 1 O-tetrahydro-4,7-dioxol 2-ol- 1 2H- cyclopenta-[2,l-g:3,4-g]diquinoline-2,9- dicarboxylic acid (I),

3. 1 ,4,7,10-tetrahydro-4,7-dioxo-12-methyl-l2-ol- 12H-cyclopenta[2,lg:3,4-g']diquinoline-2,9- dicarboxylic acid (1),

4. 1,4,7, 1 0-tetrahydro-4,7-dioxo- 1 2-ethylidene- 1 21-1- cyclopenta[2, l-g:3,4-g' ]diquinoline2,9- dicarboxylic acid (1),

5. 1,4,7,10-tetrahydro-4,7-dioxo-12-methyl-12- propyl-l2H-cyclopenta[2,1-g:3,4-g']diquinoline- 2,9-dicarboxylic acid (1), etc.,

yields, respectively,

1. di(tris-hydroxymethyl)methylammonium 1,4,7, 1 0-tetrahydro-4,7-dioxo-l 2H-cyclopenta[2, 1-g(3,4- g]diquinoline-2,9-dicarboxylic acid (1),

2. di(tris-hydroxymethyl)methylammonium l,4,7,l-

O-tetrahydro-4,7 dioxol 2-oll 2l-l-cyclopenta[2, l g:3,4-g]diquinoline-2,9-dicarboxylic acid (I),

3. di(tris-hydroxymethyl)methylammonium 1,4,7,l-

0-tetrahydro-4,7-dioxo-l2-methyl-12-ol-12H- cyclopenta[ 2, l-g:3,4-G ]-diquinoline-2,9- dicarboxylic acid (I),

4. di(tris-hydroxymethyl)methylammonium l,4,7,1-

0-tetrahydro-4,7-dioxo-12-ethylidene-l2H- cyclopenta[ 2, l -g:3,4-g ]diquinoline-2,9- dicarboxylic acid (1).

5. di(tris-hydroxymethyl)methylammonium l,4,7,1- O-tetrahydro-4,7-dioxo-l2-methyll2-propyl-12H- cyclopenta[2,1-g:3,4-g'] diquinoline-2,9- dicarboxylic acid (1), etc.

Following the procedures of the immediately preceding paragraph and of Example 1 1, but substituting for tris(hydroxy-methyl)aminomethane (in an appropriate solvent in accordance with the art, when necessary or desirable), an amine such as methylamine, dimethylamine, trimethylamineethylamine, diethylamine, triethylamine, propylamine, dipropylamine, tripropylamine, isopropylamine, diisopropylamine, triisopropylamine, ethanolamine, D-threo-2-amino-l-(p-nitrophenyl )-l ,3-propanediol, N,N-bis(hydroxyethyl)- piperazine, 2-amino-2-methyl-l-propanol, 2-amino-2- methyl-1,3-propanediol or 2,2-bis(hydroxymethyl)- 2,2,2"-nitrilotriethanol, yields the corresponding di- (substituted ammonium) salt of a 1,4,7 IO-tetrahydro- 4,7-dioxo (4,7,12 -trioxo, 4,7-dioxo-l2-ol, 4,7-dioxol2-alkyl, -12-ol, 4,7-dioxo-l2-alkylidene, or 4,7-dioxol2-lakylidene, or 4,7-dioxo-l2-dialkyl) -l2l-lcyclopenta[2,1-g:3,4 -g]diquinoline-2,9-dicarboxylic acid (I).

The compositions of the present invention are presented for administration to humans an animals in unit dosage forms, such as tablets, capsules, pills, suppositories, powders, granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions, and oilin-water and water-in-oil emulsions containing suitable quantities of the compound of Formula la. The preferred method of administration is by inhalation into the lung by means of an aerosol or powder for insufila- Mon.

For oral administration either solid or fluid unit dosage forms can be prepared. For preparing solid compositions such as tablets, the compound of Formula la is mixed with conventional ingredients such as talc, magnesium stearate, dicalcium phosphate, magnesium aluminum silicate, calcium sulfate, starch, lactose, acacia, methylcellulose, and functionally similar materials as pharmaceutical diluents or carriers. Capsules are prepared by mixing the compound with an inert pharmaceutical diluent and filling the mixture into a hard gelatin capsule of appropriate size. Soft gelatin capsules are prepared by machine encapsulation of a slurry of the compound with an acceptable vegetable oil, light liquid petrolatum or other inert oil.

Fluid unit dosage forms for oral administration such as syrups, elixirs, and suspensions can be prepared. The water-soluble forms can be dissolved in an aqueous vehicle together with sugar, aromatic flavoring agents and preservatives to form a symp. An elixir is prepared by using a hydro-alcoholic (ethanol) vehicle with suitable sweeteners such as sugar and saccharin, together with an aromatic flavoring agent.

Suspensions can be prepared with a syrup vehicle with the aid of a suspending agent such as acacia, tragacanth, methylcellulose and the like.

For parenteral administration, fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, water being preferred. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampul and sealing. Advantageously, adjuvants such as a local anesthetic, preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection is supplied to reconstitute the liquid prior to use. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration. The compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle..Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

The preferred compositions are those adapted for inhalation into the lung and containing a water soluble form of a compound of the Formula la.

Compositions for inhalation are of three basic types: l a powder mixture preferably micro-pulverized; (2) an aqueous solution to be sprayed with a neublizer; (3) an aerosol with volatile propellant in a pressurized container.

The powders are quite simply prepared by mixing a compound of the formula with a solid base which is compatible with lung tissue, preferably lactose. The powders are packaged in a device adapted to emit a measured amount of powder when inhaled through the mouth.

Aqueous solutions are prepared by dissolving the compound of the Formula la in water and adding salt to provide as isotonic solution and buffering to a pH compatible with inhalation. The solutions are dispersed in a spray device or nebulizer and sprayed into the mouth while inhaling.

Aerosols are prepared by dissolving a compound of the Formula I in water or ethanol and mixing with a volatile propellant and placing in a pressurized container having a metering valve to release a predetermined amount of material.

' The liquefied propellant employed is one which has a boiling point below 65F. at atmospheric pressure. For use in compositions intended to produce aerosols for medicinal use, the liquefied propellant should be non-toxic. Among the suitable liquefied propellants which may be employed are the lower alkanes contain ing up to five carbon atoms, such as butane and pentane, or a lower alkyl chloride, such as methyl, ethyl, or propyl chlorides. The most suitable liquefied propellants are the fluorinated and fluorochlorinated lower alkanes such as are sold underthe trademarks Freon and Genetron. Mixtures of the above-mentioned propellants may suitably be employed. Examples of these propellants are dichlorodifluoromethane (Freon l2), dichlorotetrafluoroethane (Freon 1 l4), trichloromonofluoromethane (Freon l 1), dichloromonofluormethane (Freon 21 monochlorodifluormethane (Freon 22), trichlorotrifluoroethane (Freon 113), difluoroethane (Genetron l42-A) and monochlorotrifluoromethane (Freon 13).

The term, unit dosage form, as used .in the specifiuse in humans an animals, as disclosed in detail in this specification, these being features of the present invention. Examples of suitable unit dosage forms in accord with this invention are tablets, capsules, pills, suppositories, powder packets, granules, wafers, cachets, teaspoonfuls, tablespoonfuls, dropperfuls, ampuls, vials, aerosols with metered discharges, segregated multiples of any of the foregoing, and other forms as herein described.

The dosage of the compound for treatment depends on the route of administration and the potency of the specific compound. For a single dose administered parenterally or by inhalation, a .dosage schedule of from about 0.01 to 50 mg. embraces the effective range for preventing allergic attack for which the compositions are effective. The dosage to be administered can be repeated up to 4 timesdaily. However, when it is necessary to repeat treatment, a preferred dosage schedule reduces the secondary treatment dosage to from about 0.5% to about of the above dosages, more specifically, from about 1 to about 20% of the above dosages. In this manner a state of allergy prophylaxis can be maintained. The reduced dosage is taken until that dosage no longer provides effective protection. At that T time the larger dosage is repeated, followed by the reduced dosage. An example of such a dosage schedule is the following: An asthmatic insufflates 0.5 mg. of 1,4-

. 14 ,7,l0-tetrahydro-4,7,12-trioxo-l2l-l-cyclopenta[2,1- g:3,4-g']diquinoline-2,9-dicarboxylic acid (I). After a time span of four hours the asthmatic insufflates 0.05 mg. of the same compound and every four to six hours thereafter insufflates 0.05 mg. of the same compound until effective asthma prophylaxis is not provided. The asthmatic individual then insufflates 0.5 mg. of the same compound, then reduces the insufflation dosage to 0.05 mg. four to six hours later. The dosage schedule continues in this manner. The oral dose is from about 0.1 to about 500 mg. in a single dose.

The administration of the compositions of the present invention to humans an animals provides a method for the prophylactic treatment of allergy or all anaphylactic reactions of a reagin or non-reagin mediated nature. That is to say, these compositions when administered to a sensitized individual prior to the time that the individual comes into contact with substances (anti gens), to which he is allergic, will prevent the allergic reaction which would otherwise occur.

For example, the process can be used for prophylactic treatment of such chronic conditions as bronchial asthma, allergic conjunctivitis, allergic rhinitis, food allergy, hay fever, urticaria, and auto-immune diseases.

EXAMPLE l2 A lot of 10,000 tablets, each containing 0.1 mg. of l,4,7,l0-tetrahydro-4,7,l2-trioxo-l2l-lcyclopenta[ 2, l-g:3,4-g' ]diquinoline-2,9-dicarboxylic acid (I) is prepared from the following types and amounts of ingredients:

1,4,7, 1 0-tetrahydro-4,7, l 2- trioxol 2H-cyclopental 2, l-g:3 ,4-g ldiquinoline- 2,9-dicarboxylic acid (I) l Gm. Dicalcium phosphate l,500 Gm. Methylcellulose,U.S.P. (l5 cps.) 60 Grn. Talc I50 Gm. Corn Starch 200 Gm. Calcium stearate l2 Gm.

These tablets are useful in preventing hay feverattacks at a dose of 1 tablet every four hours.

EXAMPLE 13 One thousand two-piece hard gelatin capsules, each containing mg. of l,4,7,'l0-tetrahydro-4,7,l2- trioxol 2H-cyclopenta[ 2, l-g:3,4-g' ]diquinoline-2,9- dicarboxylic acid (I) are prepared from the following types and amounts of ingredients:

1,4,7, l0-tetrahydro-4,7, l 2- 'trioxol 2H-cyclopental2, l-

g:3,4-g' ]diquinoline-2,9- dicarboxylic acid (I),

micronized Talc 100 Gm. Magnesium stearate l0 Gm.

The ingredients are mixed well and filled into capsules of the proper size.

'oxymethyl)aminomethane salt of 1,4,7,]-tetrahydro- Capsules so prepared are useful in preventing attacks of bronchial asthma at a dose of one capsule every six hours.

EXAMPLE 14 One thousand tablets, each containing 500 mg. of 1,- 4,7, 1 0-tetrahydro-4,7, l2-trioxo-1 2H-cyclopenta[2, lg:3,4-g']diquinoline-2,9-dicarboxylic acid (I) are made from the following types and amounts of ingredients:

1,4,7,l0-tetrahydro-4,7.12-trixoxoquinoline-2.9-dicarboxylic acid (1) 500 Gm. Microcrystalline cellulose NF 120 Gm. 5 Starch l6 Gm. Magnesium stearate powder 4 Gm.

The ingredients are screened and blended together and pressed into 640 mg. tablets.

The tablets are useful to protect against food allergy at a dose of 1 tablet before meals.

EXAMPLE A sterile preparation suitable for intramuscular injec- One milliliter of this sterile preparation is injected for prophylactic treatment of allergic rhinitis.

EXAMPLE l6: Aqueous Solution 600 ml. of an aqueous solution containing 0.1 mg. of the tris(hydroxymethyl)aminomethane salt of 1,4,7,10- tetrahydro-4,7,12-trioxo-l2H-cyclopenta[2,1-g:3,4- g]diquinoline-2,9-dicarboxylic acid (1) per ml. is pre- 5 pared as follows:

Tris(hydroxymethyhamino methane salt of 1,4,7, 10- tetrahydro-4,7,l2-trioxo- 12H-cyclopentu[2,l'-g: 3,4-g'|diquinoline-2.9-

V dicarboxylic acid (I) mg. Sodium chloride 5,400 mg. Water for injection q.s. 600 ml.

The THAM salt and sodium chloride and dissolved in 55 sufficient water to make 600 ml. and sterile filtered.

The solution is placed in nebulizers designed to deliver 0.25 ml. of solution per spray.

The solution is sprayed into the lungs every four hours for prevention of asthmatic attacks.

EXAMPLE l7: Powder for lnsufflation A powder mixture consisting of mg. of tris(hydr- 6 4,7,12-trioxo-12H-cyc1openta[2,1-g:3,4- 5

g]diquinoline-2,9-dicarboxylic acid (1) and sufficient lactose to make 5 gm. of mixture is micropulverized EXAMPLE 18: Aerosol Twelve of an aerosol composition is prepared from the following ingredients:

Tris( hydroxymethyl )aminomethane salt of 1,4,7,10-tetrahydro- 4,7 ,l2-trioxo-12H-cyclopenta- [2,1-g:3 ,4-g' ]diquinoline- 2,9-dicarboxy1ic acid (1) Water 4,855 Gm. Freon 12 1.43 Gm. Freon 114 5.7 Gm.

The THAM salt is dissolved in the ethanol and chilled to -30C. and added to the chilled Freons. The 12 grams of composition is added to a 13 cc. plastic coated bottle and capped with a metering valve. The metering valve releases 8 mg. of composition in an aerosol.

The aerosol is inhaled every six hours for prevention of asthmatic attacks.

The procedure described above in Examples 12 through 18 for the formulation of the compound of 1,4- ,7, 10-tetrahydro-4,7, 1 2-trioxol 2l-I-cyc1openta[2, 1- g:3,4-g']diquinoline-2,9-dicarboxy1ic acid (1) effective in the treatment of hay fever, bronchial asthma, food allergy, allergic rhinitis and asthmatic attacks (as disclosed at the end of the aforesaid examples) can also be employed in the production of medicaments providing similarly effective therapy for the aforesaid ailments wherein the active ingredient is another compound embraced by Formula 1a, e.g., dipropyl 1,4,7,1- 0-tetrahydro-4,7,l2-trioxo-l2H-cyclopenta[2,1-g:3,4- g]diquino1ine-2,9-dicarboxylate (1), dipotassium 1,4,- 7,l0-tetrahydro-4,7,12-trioxo-l2H-cyclopenta[2,lg:3,4-g' ]diquino1ine-2,9-dicarboxylate (l), diethyl 1,4,- 6,10-tetrahydro-4,7,l2-trioxo-l2H-cyc1openta[2,1- g:3,4-g ]diquinoline-2,9-dicarboxy1ate (I), dibutyl 1,4,- 7,l0-tetrahydro-4,7-dioxol 201- l 2H-cyc1openta[ 2, l-

. g:3,4-g]diquino1ine-2,9-dicarboxylate (I), disodium cyclopenta[ 2,1 -g:3,4 g ]diquinoline-2,9-dicarboxylate 1), 1,4,7,10-tetrahydro-4,7-dioxo-12-01-121-1- cyc1openta[ 2,1 -g:3,4-g ]diquinoline-2,9-dicar'boxylic acid (1), dipropyl 1,4,7,l0tetrahydro-4,7-dioxo-l2- methyl-12-o1- l 2l-l-cyclopenta[2,1-g:3 ,4- g]diquinoline-2,9-dicarboxylate (l), disodium l,4,7,1- 0-tetrahydro-4,7-dioxol 2-methy1-12-ol-l2H- cyc1openta[2,1-g:3,4-g ]diquinoline-2,9-dicarboxylate (1), 1,4,7, lO-tetrahydro-4,7-dioxol 2-methyl- 1 2-01- l2H-cyclopenta[2,1-g:3,4-g']diquino1ine-2,9 dicarboxylic acid (I), dimethyl 1,4,7,10-tetrahydro- 4,7-dioxo-121-1-cyclopenta[2, 1-g:3,4-g']diquinoline- 2,9-dicarboxylate (I), disodium l,4,7,lO-tetrahydro- 4,7-dioxo-121-1-cyc1openta[2,1-g:3,4-g]diquinoline- 2,9-dicarboxy1ate (l), 1,4,7,10-tetrahydro'4,7-dioxo- 12H-cyclopenta[2, l-g:3 ,4-g ]diquinoline-2,9- dicarboxylic acid (1), diethyl 1,4,7,10-tetrahydro-4,7- dioxo-12H-cyc1openta[2,1-g:3,4-g]diquino1ine-2,9- dicarboxylate (I), dipotassium l,4,7,l0-tetrahydro4,7- dioxo-l21-1-cyc1openta[2,1-g:3,4-g']diquinoline-2,9-

dicarboxylate (I), 1 ,4,7,10-tetrahydro-4,7-dioxo-1211- cyc1openta[2,1-g:3,4-g]diquino1ine-2,9-dicarbxylic acid (I), diisopropyl 1 ,4,7,10-tetrahydro-4,7-dioxo- 12- ethylidene-121-1-cyclopenta[2, l-g:3,4-g ]diquinoline- 2,9-dicarboxylate (I), disodium l,4,7,l-tetrahydro- 4,7-dioxol 2-ethylidenel 2H-cyclopenta[ 2, l -g:3 ,4 g ]diquinoline-2,9-dicarboxylate (I), 1,4,7, 1 O- tetrahydro-4,7dioxol 2-ethylidene- 1 2H- cyclopenta[ 2 l -g: 3 ,4-g' ]diquinoline-2,9-dicarboxylic acid (I), 1,4,7,l0-tetrahydro-4,7-dioxo-l2-ethyl-12H- cyclopenta[ 2, lg: 3,4-g' ]diquinoline-2,9-dicarboxylate acid (I), I ,4,7, l O-tetrahydro-4,7-dioxol 2-ethyll 2- methyl- 1 2l-I-cyclopenta[ 2, l-g: 3 ,4-g' ]diquinoline-2,9- dicarboxylic acid (I), l,4,7,l0-tetrahydro-4,7-dioxo- 12-methyl-l2-propyl-l2H-cyclopenta[2,l-g:3,4- gldiquinoline-2,9-dicarboxylic acid (I), di(tris-hydroxymethyl)-methyl ammonium l,4,7,l0- tetrahydro-4,7, l 2-trioxo-l 2I-I-cyclopenta[ 2, 1 -g:3,4- g]diquinoline-2,9-dicarboxylic acid (I), di(trishydroxymethyl )methylammonium 1,4,7, tetrahydro-4,7-dioxol 2H-cyclopenta[ 2, l-g:3 ,4- g']diquinoline-2,9-dicarboxylic acid (I), di(tris)- hydroxymethyl)methylammonium l ,4,7,10- tetrahydro-4,7-di0xol 2-oll 2H-cyclopenta[ 2, l -g:3 ,4- g']diquinoline-2,9-dicarboxylic acid (I), di(trishydroxymethyl )methylammonium 1 ,4,7,10- tetrahydro-4,7-dioxol 2-methyl- I 2-ol 1 2H- cyclopenta[2,1-g:3,4-g'1diquinoline-2,9-dicarboxylic acid (I), dimethylammonium l,4,7,lO-tetrahydro- 4,7,12-trioxo-l2H-cyclopenta[2, l-g:3,4- g ldiquinoline-2,9-dicarboxylic acid (I), di(triethylammonium) l ,4,7, l 0-tetrahydro-4,7,-dioxol 2-methyll2-oll 2H-cyclopenta[ 2, l -g:3,4-g ]diquinoline-2,9- dicarboxylic acid (I), di[D-thre0-2-amino-l-(p-nitrophenyl)- l ,3propanediol] ammonium l ,4,7,10- tetrahydro-4,7-dioxol 2H-cyclopenta[2, l-g:3,4- g]diquinoline-Z,9-dicarboxylic acid (I), etc.

We claim:

l. A compound of the formula wherein R and R are selected from the group consisting of hydrogen and lower alkyl of I through 6 carbon atoms 2. A compound of claim 1 wherein R and Z are hydrogen and A is namely, 1 ,4,7,l0-tetrahydro-4,7,l2-trioxo-12H- cyclopenta[2,l-g:3,4-g]diquinoline-2,9-dicarboxy1ic acid.

' 3. A compound of claim I wherein R is the cation of tris(hydroxymethyl)-aminomethane and Z is hydrogen and A is namely, di(tris-(hydroxymethyl))methylammonium 1,4,7, 1 O-tetrahydro-4,7 l 2-trioxo- 1 2H- cyclopenta[ 2, l -g: 3 ,4-g ]diquinoline-2,9dicarboxylate. l 

2. A compound of claim 1 wherein R and Z are hydrogen and A is
 3. A compound of claim 1 wherein R is the cation of tris(hydroxymethyl)-aminomethane and Z is hydrogen and A is 